Autoimmunity
Abstract
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II-restricted model peptide in hepatocytes by autoreactive CD4 T cells. We find that the hepatic peptide was not expressed in the thymus leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4 T cells. In the liver, autoreactive CD4 effector T cells accumulated within portal ectopic lymphoid structures and maturated towards pathogenic IFNγ and TNF co-producing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs, but not of non-specific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared to non-specific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.
Authors
Max Preti, Lena Schlott, David Lübbering, Daria Krzikalla, Anna-Lena Müller, Fenja A. Schuran, Tobias Poch, Miriam Schakat, Sören Weidemann, Ansgar W. Lohse, Christina Weiler-Normann, Marcial Sebode, Dorothee Schwinge, Christoph Schramm, Antonella Carambia, Johannes Herkel
Abstract
Tenascin-C, an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis. In this study, we utilized a systematic discovery process and identified five novel citrullinated tenascin-C (cit-TNC) T cell epitopes. CD4+ T cells specific for these epitopes were elevated in the peripheral blood of subjects with rheumatoid arthritis and showed signs of activation. Cit-TNC-specific T cells were also present among synovial fluid T cells and secreted interferon-γ. Two of these cit-TNC peptides were recognized by antibodies within the serum and synovial fluid of individuals with RA. Detectable serum levels of cit-TNC reactive antibodies were prevalent among subjects with RA and positively associated with cyclic citrullinated peptide (CCP) reactivity and the HLA shared epitope. Furthermore, cit-TNC reactive antibodies were correlated with rheumatoid factor and elevated in subjects with a history of smoking. Taken together this work confirms cit-TNC as an autoantigen that is targeted by autoreactive CD4+ T cells and autoantibodies in patients with RA. Furthermore, our findings suggest that a unique set of epitopes recognized by both CD4+ T cells and B cells have the potential to amplify autoimmunity and promote the development and progression of rheumatoid arthritis.
Authors
Jing Song, Anja Schwenzer, Alicia Wong, Sara Turcinov, Cliff Rims, Lorena Rodríguez-Martínez, David Arribas-Layton, Christina Gerstner, Virginia S. Muir, Kim S. Midwood, Vivianne Malmström, Eddie A. James, Jane H. Buckner
Abstract
Reestablishing an appropriate balance between T effector cells (Teff) and T regulatory cells (Treg) is essential for correcting autoimmunity. Multiple Sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teff cells, Th1 and Th17 cells. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4 T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest selective inhibition of STAT3 by the novel small molecule LLL12b recalibrates the effector and regulatory arms of CD4 T responses, representing a potentially clinically translatable therapeutic strategy for MS.
Authors
Saba I. Aqel, Xiaozhi Yang, Emma E. Kraus, Jinhua Song, Marissa F. Farinas, Erin Y. Zhao, Wei Pei, Amy E. Lovett-Racke, Michael K. Racke, Chenglong Li, Yuhong Yang
Abstract
Ginger is known to have anti-inflammatory and anti-oxidative effects, and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report anti-neutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to demonstrate a protective role for ginger-derived compounds in the context of lupus, and importantly provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.
Authors
Ramadan A. Ali, Alex A. Gandhi, Lipeng Dai, Julia K. Weiner, Shanea K. Estes, Srilakshmi Yalavarthi, Kelsey Gockman, Duxin Sun, Jason S. Knight
Abstract
Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic beta cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent onset T1D, endogenous insulin production was preserved in 30% of subjects for two years post-therapy. Given our previous findings linking exhausted CD8 T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8 T cells to evaluate their potential role in T1DAL. Using RNA-seq, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into two distinct CD8 memory populations through correlation with clustered cytometry data. Both populations were hypo-proliferative, shared expanded TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The populations were distinguished by reciprocal expression of CD8 T and NK cell markers (GZMB, CD57 and inhibitory KIR genes), versus T cell activation and differentiation markers (PD1 and CD28). These findings support previous evidence linking exhausted CD8 T cells to successful immune interventions for T1D, while suggesting multiple inhibitory mechanisms can promote this beneficial cell state.
Authors
Kirsten E. Diggins, Elisavet Serti, Virginia S. Muir, Mario G. Rosasco, TingTing Lu, Elisa Balmas, Gerald T. Nepom, S. Alice Long, Peter S. Linsley
Abstract
Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse T1D. In this study, using Cox model multivariate analysis we validate our previous findings that patients (n = 84) with the highest frequency of CD4+ CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission and we show that the 127-hi cell population is a mix of Th1- and Th2-type cells with a significant bias towards anti-inflammatory Th2-type cells. In addition, we extend these findings to show that patients with the highest frequency of 127-hi cells at diagnosis are significantly more likely to maintain beta-cell function. Moreover, in patients treated with Alefacept in the TIDAL clinical trial, the probability of responding favorably to the anti-inflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an anti-inflammatory environment that is permissive for partial remission, beta-cell survival and response to anti-inflammatory immunotherapy.
Authors
Aditi Narsale, Breanna Lam, Rosita Moya, TingTing Lu, Alessandra Mandelli, Irene Gotuzzo, Benedetta Pessina, Gian Maria Giamporcaro, Rhonda Geoffrey, Kerry Buchanan, Mark Harris, Anne-Sophie Bergot, Ranjeny Thomas, Martin J. Hessner, Manuela Battaglia, Elisavet Serti, Joanna D. Davies
Abstract
The brain ventricles are part of the fluid compartments bridging the CNS with the periphery. Using MRI, we previously observed a pronounced increase in ventricle volume (VV) in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here, we examined VV changes in EAE and MS patients in longitudinal studies with frequent serial MRI scans. EAE mice underwent serial MRI for up to 2 months, with gadolinium contrast as a proxy of inflammation, confirmed by histopathology. We performed a time-series analysis of clinical and MRI data from a prior clinical trial in which RRMS patients underwent monthly MRI scans over 1 year. VV increased dramatically during preonset EAE, resolving upon clinical remission. VV changes coincided with blood-brain barrier disruption and inflammation. VV was normal at the termination of the experiment, when mice were still symptomatic. The majority of relapsing-remitting MS (RRMS) patients showed dynamic VV fluctuations. Patients with contracting VV had lower disease severity and a shorter duration. These changes demonstrate that VV does not necessarily expand irreversibly in MS but, over short time scales, can expand and contract. Frequent monitoring of VV in patients will be essential to disentangle the disease-related processes driving short-term VV oscillations from persistent expansion resulting from atrophy.
Authors
Jason M. Millward, Paula Ramos Delgado, Alina Smorodchenko, Laura Boehmert, Joao Periquito, Henning M. Reimann, Christian Prinz, Antje Els, Michael Scheel, Judith Bellmann-Strobl, Helmar Waiczies, Jens Wuerfel, Carmen Infante-Duarte, Andreas Pohlmann, Frauke Zipp, Friedemann Paul, Thoralf Niendorf, Sonia Waiczies
Abstract
A possible etiological link between the onset of endemic pemphigus in Tunisia and bites of Phlebotomus (P). papatasi, the vector of zoonotic cutaneous leishmaniasis has been previously suggested. We hypothesized that the immunodominant P. papatasi salivary protein PpSP32 binds to desmogleins (Dsg1 and Dsg3), triggering loss of tolerance to these pemphigus target autoantigens. We here show by Far-Western blot that the recombinant PpSP32 protein (rPpSP32) binds to epidermal proteins with a molecular weight of about 170kDa. Co-immunoprecipitation revealed the interaction of rPpSP32 with either Dsg1 or Dsg3. A specific interaction between PpSP32 and Dsg (1 and 3) was further demonstrated by ELISA assays. Finally, mice immunized with rPpSP32 twice a week exhibited significantly increased levels of anti-Dsg1 and anti-Dsg3 antibodies from day 75 to day 120. Such antibodies were specific for Dsg1 and Dsg3 and were not the result of crossreactivity to PpSP32. Herein, we demonstrated for the first time a specific binding between the PpSP32 and the dsg1 and 3, which might underlie the triggering of anti-Dsg antibodies in patients exposed to sand fly bites. We also confirmed the development of specific anti-Dsg1 and -Dsg3 antibodies in vivo after PpSP32 immunization in mice. Collectively, our results provide evidence that environmental factors, such the exposure to P. papatasi bites, can trigger the development of autoimmune antibodies.
Authors
Soumaya Marzouki, Ines Zaraa, Maha Abdeladhim, Chaouki Ben Abdessalem, Fabiano Oliveira, Shaden Kamhawi, Mourad Mokni, Hechmi Louzir, Jesus Valenzuela, Mélika Ben Ahmed
Abstract
Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in two CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African-American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African-American and European-American lupus patients include type I interferon-response genes such as IRF7 and IFI44, and genes related to the NFkB pathway. TREML4, which plays a vital role in toll-like receptor signaling, was hypomethylated in African-American patients and demonstrated a strong cis-meQTL effect among 8855 cis-meQTL associations identified in our study.
Authors
Patrick Coit, Lourdes Ortiz-Fernandez, Emily E. Lewis, W. Joseph McCune, Kathleen Maksimowicz-McKinnon, Amr H. Sawalha
Abstract
Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3–IL-17+ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15+ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15+ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.
Authors
Wan-Chen Hsieh, Mattias N.D. Svensson, Martina Zoccheddu, Michael L. Tremblay, Shimon Sakaguchi, Stephanie M. Stanford, Nunzio Bottini
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